Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 203-560-6 | CAS number: 108-20-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
Diisopropyl ether as well as the surrogate ethyl tert.-butyl ether were assessed in one generation reproductive toxicity studies (application by whole body inhalation exposure) for effects on fertility and developmental toxicity with exposure up to 20.000 mg/m³ (tested in gasoline as diluent, equivalent to 3560 mg/m³ DIPE) and no effects of fertility or sexual performance were seen. The two studies in DIPE and ETBE showed absolutely comparable results in absence of reproductive effects and slight parental findings with respect to increased liver weights, leading to a NOAEC of 2000 mg/m³ for parental effects and 20.000 mg/m³ (highest dose group) for reproductive effects.
In addition, ethyl tert.-butyl ether (ETBE) had been assessed in a two-generation reproductive toxicity study in rats by oral exposure with doses up to 1000 mg/kg bw/d and no effects on fertility were seen in this study. Changes in absolute and relative kidney weights lead to a parental NOAEL of 250 mg/kg bw/d in this study, showing slight toxicity to parental animals, but no effects on mating, fertility, gestation, fecundity or delivery on sperm parameters were observed. The identical findings of DIPE in gasoline and ETBE in gasoline as well as the structural similarity of the two substances, both being ethers of identical molecular weight and very similar phys-chem properties, do support ETBE being a reliable surrogate for DIPE and the finding in the two-generation reproductive toxicity study, showing no effects on reproductive parameters support the absence of necessity to investigate further on reproductive toxicity of DIPE.
Link to relevant study records
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- read-across source
- Vehicle:
- other: see source study
- Duration of treatment / exposure:
- see source study
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no remarkable clinical observations reported
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Light hydrocarbon nephropathy was strongly indicated in all studies by the presence of hyaline droplets in kidneys of 20,000 mg/m³ male rats, an effect already known for decade attributable to the hydrocarbon carrier.
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- Estrus cyclicity parameters were comparable between exposed and concurrent control groups.
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- Semen parameters were comparable between exposed and concurrent control groups.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There were no differences in male and female fertility or reproductive performance with exposure to any test material.
- Dose descriptor:
- NOAEC
- Effect level:
- 2 000 mg/m³ air (nominal)
- Based on:
- test mat. (total fraction)
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- Remarks on result:
- other: Parental effect
- Dose descriptor:
- NOAEC
- Effect level:
- 20 000 mg/m³ air (nominal)
- Based on:
- test mat. (total fraction)
- Sex:
- male/female
- Remarks on result:
- other: Reproductive parameters
- Remarks:
- No effects
- Dose descriptor:
- NOAEC
- Effect level:
- 356 mg/m³ air (analytical)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- Remarks on result:
- other: Parental effects
- Remarks:
- calculated as DIPE
- Dose descriptor:
- NOAEC
- Effect level:
- 3 560 mg/m³ air (analytical)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: no effects
- Remarks on result:
- other: Reproductive parameters
- Remarks:
- calculated as DIPE
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No adverse effects were seen on offspring organ weights
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no findings of malformations
- Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- no effects observed
- Developmental immunotoxicity:
- not examined
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- 20 000 mg/m³ air (nominal)
- Based on:
- test mat. (total fraction)
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Reproductive effects observed:
- no
- Conclusions:
- In this one generation reproductive toxicity study with a gasoline blend supplemented by 17.8% di-isopropyl ether (measured in vapour phase), no developmental effects or decreases in fertility were observed and thus the NOAEC in this study was set to the highest does tested being 20.000 mg/m³. The addition of di-isopropylether in significant amounts had no impact on reproductive toxicity of oxygenated fuels and hence it is concluded that DIPE as such does not have negative developmental/reproductive effects.
- Executive summary:
Vapour condensates of baseline gasoline (BGVC), or gasoline-blended with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for reproductive toxicity in rats at target concentrations of 2000, 10,000, or 20,000 mg/m³, 6 h/day, 7 days/week. BGVC and G/MTBE were assessed over two generations, the others for one generation. BGVC and G/MTBE F1 offspring were evaluated for neuropathology and changes in regional brain glial fibrillary acidic protein content. No neurotoxicity was observed. Male kidney weight was increased consistent with light hydrocarbon nephropathy. In adult rats, decreased body weight gain and increased liver weight were seen. Spleen weight decreased in adults and pups exposed to G/TBA. No pathological changes to reproductive organs occurred in any study.
Decreased food consumption was seen in G/TAME lactating females. Transient decreases in G/TAME off-spring weights were observed during lactation. Except for a minor increase in time to mating in G/TBA which did not affect other reproductive parameters, there were no adverse reproductive findings. The NOAEL for reproductive and offspring parameters was 20,000 mg/m³ for all vapour condensates except for lower offspring NOAELs of 10,000 mg/m³ for G/TBA and 2000 mg/m³ for G/TAME.
Thus, it can be concluded that di-isopropyl ether did not impact reproductive toxicity in this one-generation reproductive toxicity study. Similar finding were made with other ethers used in the same study setup such as methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), and t-amyl methyl ether (G/TAME).
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Reason / purpose for cross-reference:
- read-across source
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no remarkable clinical observations reported
- Dermal irritation (if dermal study):
- not examined
- Description (incidence and severity):
- Inhalation exposure, therefore, dermal effect not monitored
- Mortality:
- no mortality observed
- Description (incidence):
- There were no significant effects of treatment on survival in the study.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- Statistically significant reduction in weight gain during the premating period was observed in females exposed to 20,000 mg/m³ BGVC (P0) G/MTBE (P0 and F1), G/ETBE and G/TBA. No effects on maternal body weight gains occurred during gestation (GD 0 – 20) and lactation (LD 1 – 28). Among males, decreased body weight changes were seen in parental animals in G/ETBE and G/TBA.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- Food consumption was comparable to concurrent controls
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not specified
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No remarkable histopathologic changes were reported in the study.
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Light hydrocarbon nephropathy was strongly indicated in all studies by the presence of hyaline droplets in kidneys of 20,000 mg/m³ male rats, an effect already known for decade attributable to the hydrocarbon carrier.
- Reproductive function: oestrous cycle:
- no effects observed
- Description (incidence and severity):
- Estrus cyclicity parameters were comparable between exposed and concurrent control groups.
- Reproductive function: sperm measures:
- no effects observed
- Description (incidence and severity):
- Semen parameters were comparable between exposed and concurrent control groups.
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- There were no differences in male and female fertility or reproductive performance with exposure to any test material.
- Dose descriptor:
- NOAEC
- Effect level:
- 2 000 mg/m³ air (nominal)
- Based on:
- test mat. (total fraction)
- Sex:
- male/female
- Basis for effect level:
- organ weights and organ / body weight ratios
- Remarks on result:
- other: Parental effect
- Dose descriptor:
- NOAEC
- Effect level:
- 20 000 mg/m³ air (nominal)
- Based on:
- test mat. (total fraction)
- Sex:
- male/female
- Remarks on result:
- other: Reproductive parameters
- Remarks:
- No effects
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No adverse effects were seen on offspring organ weights
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- There were no findings of malformations
- Histopathological findings:
- not specified
- Other effects:
- not specified
- Behaviour (functional findings):
- no effects observed
- Developmental immunotoxicity:
- not examined
- Dose descriptor:
- NOAEC
- Generation:
- F1
- Effect level:
- 20 000 mg/m³ air (nominal)
- Based on:
- test mat. (total fraction)
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Reproductive effects observed:
- no
- Conclusions:
- In this one generation reproductive toxicity study with a gasoline blend containing 16.3% ethyl tert.-butyl ether (ETBE), no developmental effects or decreases in fertility were observed and thus the NOAEC in this study as set to the highest does tested being 20.000 mg/m³.
- Executive summary:
Vapour condensates of baseline gasoline (BGVC), or gasoline-blended with methyl tertiary butyl ether (G/MTBE), ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA) were evaluated for reproductive toxicity in rats at target concentrations of 2000, 10,000, or 20,000 mg/m³, 6 h/day, 7 days/week. BGVC and G/MTBE were assessed over two generations, the others for one generation. BGVC and G/MTBE F1 offspring were evaluated for neuropathology and changes in regional brain glial fibrillary acidic protein content. No neurotoxicity was observed. Male kidney weight was increased consistent with light hydrocarbon nephropathy. In adult rats, decreased body weight gain and increased liver weight were seen. Spleen weight decreased in adults and pups exposed to G/TBA. No pathological changes to reproductive organs occurred in any study.
Decreased food consumption was seen in G/TAME lactating females. Transient decreases in G/TAME off-spring weights were observed during lactation. Except for a minor increase in time to mating in G/TBA which did not affect other reproductive parameters, there were no adverse reproductive findings. The NOAEL for reproductive and offspring parameters was 20,000 mg/m³ for all vapour condensates except for lower offspring NOAELs of 10,000 mg/m³ for G/TBA and 2000 mg/m³ for G/TAME.
Thus, it can be concluded that ethyl tert.butyl ether (ETBE) did not impact reproductive toxicity in this one-generation reproductive toxicity study. The findings using DIPE supplemented gasoline (17.8 % (v/v)) at ETBE supplemented gasoline (16.3 % (v/v)) were fully comparable, supporting the ypproach to use reproductive toxicity data from ETBE as read-across source to DIPE.
- Endpoint:
- two-generation reproductive toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- test procedure in accordance with generally accepted scientific standards and described in sufficient detail
- Reason / purpose for cross-reference:
- read-across source
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- Inhalation exposure, therefore, dermal effect not monitored
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- No remarkable histopathologic changes were reported in the study.
- Other effects:
- no effects observed
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 250 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: statistically significant reduction in body weight gain in F0 males, absolute and relative kidney weight increased in F0 and F1 males and absolute and relative liver weights in F1 males
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to adverse toxic effects at highest dose / concentration tested
- Reproductive effects observed:
- no
- Conclusions:
- The results from the study on ETBE can nominally be converted to DIPE as molecular weights of the two substances are identical. The NOAEL (P1) was set to 250 mg/kg bw/d, based on statistically significant reduction in body weight gain in F0 males, absolute and relative kidney weight increased in F0 and F1 males and absolute and relative liver weights in F1 males. The NOAEL for fertility was set to 1000 mg/kg bw/d (highest dose applied) due to lack of effects on mating, fertility, gestation, fecundity, delivery or sperm parameters. No effects were observed on the progeny from delivery until weaning. The NOEL for F1 and F2 generation were set to 1000 mg/kg bw/d, as no treatment-related or statistically significant changes were seen in pups found dead or sacrificed early, or in pups subject to scheduled necropsy at weaning.
Referenceopen allclose all
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- chronic
- Species:
- rat
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 3 560 mg/m³
- Study duration:
- subchronic
- Species:
- rat
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
In accordance with column 2 of REACH Annex VIII, the reproductive toxicity screening study (required in section 8.7.1) does not need to be conducted as a pre-natal developmental toxicity study is available.
A 13-week repeated dose toxicity study by Dalbey and Feuston (1996) noted that the number of sperm and spermatids were not changed; however, there was a significant change in number of abnormal sperm at 7100 ppm. The authors noted that the change in number of abnormal sperm was not considered to be biologically significant. No information is available for the effects on sexual function and fertility in adult females from this study.
Recently, results from one- and two-generation studies assessing effects of oxygenates, supplemented to gasoline, were published. In this study, baseline gasoline and one representative (methyl tert.-butyl ether MTBE) were assessed in a two-generation reproductive toxicity study design, whereas other gasoline blend with oxygenates (ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA)) were investigated in a one-generation study design, applying exposure via inhalation (whole body, 6h/day, 7 days/week). In these investigations no effects on fertility or developmental toxicity were found when dosed up to 20.000 mg/m³, equivalent to 3560 mg/m³ pure DIPE. ETBE, investigated in the same study, also did not show any effects on fertility and developmental toxicity, which supports the validity of the read-across hypothesis to use ETBE reproductive toxicity data as surrogate data to assess DIPE reproductive toxicity. Thus, the results from a two-generation reproductive toxicity study in rats by oral exposure with doses up to 1000 mg/kg bw/d and no effects on fertility seen in this study, can be used for read-across to DIPE too. Changes in absolute and relative kidney weights lead to a parental NOAEL of 250 mg/kg bw/d in this study, showing slight toxicity to parental animals, but no effects on mating, fertility, gestation, fecundity or delivery on sperm parameters were observed. The identical findings of DIPE in gasoline and ETBE in gasoline as well as the structural similarity of the two substances, both being ethers of identical molecular weight and very similar phys-chem properties, do support ETBE being a reliable surrogate for DIPE and the finding in the two-generation reproductive toxicity study, showing no effects on reproductive parameters support the absence of reproductive effects of DIPE and indicate no necessity to investigate further on reproductive toxicity of DIPE.
Effects on developmental toxicity
Description of key information
An inhalation prenatal development toxicity study of di-isopropyl ether (DIPE) in rats, equivalent to OECD guideline 414, did not report a NOAEC. However, based on a review of the data, the NOAEC for maternal and developmental toxicity was considered to be 430 ppm (1800 mg/m³). A concentration-related increase in the incidence of fetal rudimentary 14th ribs was noted at maternal toxic doses of DIPE. The study authors indicated that the rib findings were not indicative of teratogenicity. There were no embryotoxic effects reported.
Results from one- and two-generation studies assessing effects of oxygenates, supplemented to gasoline, also do support the absence of developmental effects in rats. In this study, baseline gasoline and one representative (methyl tert.-butyl ether MTBE) were assessed in a two-generation reproductive toxicity study design, whereas other gasoline blend with oxygenates (ethyl t-butyl ether (G/ETBE), t-amyl methyl ether (G/TAME), diisopropyl ether (G/DIPE), ethanol (G/EtOH), or t-butyl alcohol (G/TBA)) were investigated in a one-generation study design, applying exposure via inhalation (whole body, 6h/day, 7 days/week). In these investigations no effects on fertility or developmental toxicity were found when dosed up to 20.000 mg/m³, equivalent to 3560 mg/m³ pure DIPE. ETBE, investigated in the same study, also did not show any effect on fertility and developmental toxicity, which supports the validity of the read-across hypothesis to use ETBE reproductive toxicity data as surrogate data to assess DIPE reproductive toxicity.
A study investigating the developmental toxicity to rabbits via oral exposure from ETBE (ethyl tert.-butyl ether) also did not indicate any developmental toxicity, and as outlined above, ETBE is a suitable surrogate for assessing developmental toxicity of DIPE. Thus, it can be concluded that generation of additional data for developmental toxicity in a second species (besides rats) can be omitted for animal welfare reasons.
Link to relevant study records
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1996
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- GLP compliance:
- no
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, NY
- Age at study initiation: Rats were approximately 9 weeks old when received and approximately 11 weeks old when breeding began
- Weight at study initiation: Not reported
- Fasting period before study: None
- Housing: Individually housed in 1 cubic metre (H-1000) inhalation chambers.
- Diet (e.g. ad libitum): Certified Purina Rodent Chow 5002 ad libitum except during exposure period
- Water (e.g. ad libitum): Ad libitum except during exposure period
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 to 22 ºC
- Humidity (%): 40 to 60%
- Air changes (per hr): At least 12/hour
- Photoperiod (hrs dark / hrs light): 12 hours: 12 hours - Route of administration:
- inhalation: vapour
- Type of inhalation exposure (if applicable):
- whole body
- Vehicle:
- unchanged (no vehicle)
- Details on exposure:
- GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: H-1000 1 cubic-metre chambers
- Source and rate of air: HEPA-filtered room air; rate of air flow = 290 lpm
- Temperature, humidity, pressure in air chamber: Mean temperature within the chambers was in the range of 23 to 24 ºC and relative humidity was 60 to 67%. Pressure was not reported.
- Air flow rate: 290 lpm
- Air change rate: 12 changes/hour
- Treatment of exhaust air: Air exiting the chambers was cleaned by passage through charcoal beds
TEST ATMOSPHERE
- Brief description of analytical method used: Samples of air (approximately 50 to 250 µL) from the chambers were drawn into a gas-tight syringe and the air was injected directly into a gas chromatograph with a flame ionization detector and a fused silica column. In addition, 500 µL samples of air from the chambers were periodically taken for analysis by gas chromatography/mass spectroscopy.
VEHICLE (if applicable)
- Justification for use and choice of vehicle: No vehicle - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples of air (approximately 50 to 250 µL) from the chambers were drawn into a gas-tight syringe and the air was injected directly into a gas chromatograph with a flame ionization detector and a fused silica column. Analyzed concentrations included both DIPE and total hydrocarbons. In addition, 500 µL samples of air from the chambers were periodically taken for analysis by gas chromatography/mass spectroscopy. Time points of analysis were not reported.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1
- Length of cohabitation: Not reported
- Proof of pregnancy: sperm plug/sperm in the vaginal lavage fluid referred to as day 0 of pregnancy - Duration of treatment / exposure:
- 6 hours/day on Days 6 to 15 of gestation
- Frequency of treatment:
- 6 hours/day on Days 6 to 15 of gestation
- Duration of test:
- Approximately 5 weeks (acclimation = 2 weeks and study duration = approximately 3 weeks)
- Dose / conc.:
- 430 ppm (analytical)
- Remarks:
- equivalent to 1800 mg/m³, basis analytical conc.
- Dose / conc.:
- 3 095 ppm (analytical)
- Remarks:
- equivalent to 12940 mg/m³, basis analytical conc.
- Dose / conc.:
- 6 745 ppm (analytical)
- Remarks:
- equivalent to 28200 mg/m³, basis analytical conc.
- No. of animals per sex per dose:
- 22 females/group
- Control animals:
- yes, concurrent no treatment
- yes, sham-exposed
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily
DETAILED CLINICAL OBSERVATIONS: No data
BODY WEIGHT: Yes
- Time schedule for examinations: Recorded on Days 0, 6, 13, 16, and 20.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Not applicable
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: Publication states that "all organs were examined grossly;" however, specific organs were not reported. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: No data - Statistics:
- ANOVA, Fisher's exact, or Dunnett's tests were used
- Indices:
- None reported
- Historical control data:
- None reported
- Details on maternal toxic effects:
- Maternal toxic effects: yes
Details on maternal toxic effects:
Lacrimation and salivation were noted in a few DIPE-exposed females at the highest concentration during, or immediately following, exposures. The animals returned to normal appearance shortly after cessation of each daily exposure.
In general, animals housed in chambers gained less weight and consumed less food during the exposure period than the untreated controls (statistically significant at 6745 ppm relative to both of the control groups).
No treatment-related effects were noted at the time of macroscopic examination.
Serum chemistry endpoints were not adversely affected by exposure to DIPE vapors.
Statistically significant decrease in body weight gains were seen on gestation days 6 to 16 at all dose levels (compared to untreated controls for the low- and mid-dose groups and compared to both controls at the high-dose group).
Statistically significant decrease was seen in food consumption on gestation days 6 to 16 at the mid- and high-dose groups (compared to untreated controls on gestation days 6 to 13 and compared to both control groups on gestation days 13 to 16).
Reproductive parameters (i.e., number of pregnant females, percent preimplantation loss, percent resorptions, and litter sizes) were not affected by exposure. - Dose descriptor:
- NOEC
- Effect level:
- 430 ppm (analytical)
- Based on:
- test mat. (dissolved fraction)
- Basis for effect level:
- other: maternal toxicity
- Remarks on result:
- not determinable
- Remarks:
- no NOAEC identified by the authors, as these effects were considered transient and non-adverse by the authors arguing that this "variation" is not conclusive evidence of developmental toxicity
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Fetal development (i.e., fetal body weight) was not affected by exposure.
Evaluations of fetal skeletons revealed a significant increase in rudimentary (small, discrete ossification) or short (less than one-half the length of the preceding rib) 14th ribs in fetuses exposed to DIPE at concentrations of 3095 and 6745 ppm. All of the observed 14th ribs were rudimentary except for 2 fetuses from each of the mid- and high-dose groups that had either bilateral short 14th ribs or bilateral short and rudimentary 14th ribs. No other exposure-related findings were noted at the time of fetal evaluations. The study authors have stated that "the observed increase in the incidence of rudimentary 14th ribs does not appear to be indicative of an adverse effect on development" at the concentrations tested. - Dose descriptor:
- NOEC
- Effect level:
- 430 ppm (analytical)
- Based on:
- test mat. (dissolved fraction)
- Sex:
- male/female
- Basis for effect level:
- other: slight skeletal effects
- Remarks on result:
- other: no NOAEC identified by the authors, as these effects were considered transient and non-adverse by the authors arguing that this "variation" is not conclusive evidence of developmental toxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
- Conclusions:
- No developmental effects in the absence of maternal toxicity were observed. The NOAEC in this study for maternal effects as well as developmental effects can be set to 430 ppm.
- Executive summary:
A NOAEC was not reported by the study authors. Review of the study data suggests that a NOAEC of 430 ppm can be derived for maternal toxicity based on the decrease in body weight gain and food consumption at higher concentrations, and a NOAEC of 430 ppm can be derived for foetal toxicity based on increases in rudimentary/short 14th ribs at higher concentrations (although the authors argue that this "variation" is not conclusive evidence of developmental toxicity).
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reason / purpose for cross-reference:
- read-across source
- Reason / purpose for cross-reference:
- read-across: supporting information
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: developmental toxicity
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: fetotoxicity
- Developmental effects observed:
- no
Referenceopen allclose all
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rabbit
- Quality of whole database:
- the study is supported by equivalent finding (no effects at 1000 mg/kg bw/d) in rats (OECD 414) study
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEC
- 1 800 mg/m³
- Species:
- rat
- Quality of whole database:
- the study is supported by equivalent finding (no effects at 3560 mg DIPE/m³) in rats (one generation reproductive toxicity study).
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
The effect of diisopropyl ether (DIPE) on fetal development was evaluated in a prenatal development toxicity study that was similar to OECD test guideline 414 (Dalbey and Feuston, 1996). The GLP-compliance of the study was not specified in the publication. DIPE was administered by whole body inhalation to timed-pregnant Wistar rats at concentrations of 0 (untreated), 0 (sham exposed), 430, 3095, or 6745 ppm (1800, 12940, or 28200 mg/m3) for 6 hours a day from gestation days 6 through 15 (n = 22/group). Decreased body weight gain was reported in DIPE and sham-treated animals compared to controls. Maternal body weight gain was statistically significantly decreased at 6745 ppm compared to both control groups. Maternal food consumption was statistically significantly decreased in the 3095 and 6745 ppm dose groups compared to both control groups. There were no effects of DIPE on embryotoxicity parameters or on fetal body weight. An increase in rudimentary (small, discrete ossification) or short (less than one-half the length of the preceding rib) 14th ribs was reported in fetuses in the 3095 and 6745 ppm groups. Given that no other teratogenic findings were observed when the dose was doubled from 3095 to 6745 ppm, the authors argued that these findings were not indicative of teratogenicity. The authors of the publication did not identify a NOAEC for maternal or developmental toxicity; however, based on these data, the NOAEC for maternal and developmental toxicity in rats was considered to be 430 ppm (1800 mg/m³).
Additionally, data on gasoline vapour exposure of rats, supplemented by di-isopropyl ether (17.8% v/v) and ethyl tert.-butyl ether (16.3% v/v) in a one-generation reproductive toxicity study design showed, that no effects on fertility were seen, but also no effects on developmental toxicity. The NOAEL in these studies for developmental toxicity were 20.000 mg/m³ (equivalent to 3560 mg DIPE/m³). An oral developmental toxicity study, performed by gavage exposure of rabbits during GD 6 - 29 to ETBE up to 1000 mg/kg bw/d also did not indicate any developmental toxicity effects.
In summary, it can be concluded that all available studies on developmental toxicity, resulting from OECD 414 studies on rats and rabbits, as well as resulting from OECD 416 studies on rats, do indicate that no developmental toxicity is to be expected from oral or inhalation exposure to di-isopropyl ether.
Justification for classification or non-classification
The fertility and developmental toxicity studies indicate that DIPE does not affect reproductive toxicity. All available studies on reproductive toxicity do indicate no reproductive toxicity from oral or inhalation exposure to di-isopropyl ether. As a result, data is conclusive not to classify DIPE according to Regulation (EC) No 1272/2008, Annex I section 3.7 for reproductive toxicity.
Additional information
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.